Diverse effects of P-glycoprotein inhibitory agents on human leukemia cells expressing the multidrug resistance

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G Lehne1, L Mørkrid, M den Boer

  • 1Department of Clinical Pharmacology, Institute for Surgical Reseach, The National Hospital, Rikshospitalet, University of Oslo, Norway.

International Journal of Clinical Pharmacology and Therapeutics
|April 28, 2000
PubMed
Abstract

Insights

Novel agents PSC 833, 280-446, and LY335979 show varied effects on multidrug resistance (MDR) in cancer cells. While effective against P-glycoprotein (Pgp) mediated resistance, only PSC 833 and 280-446 also impact multidrug resistance protein (MRP) activity.

Area of Science:

  • Pharmacology
  • Cancer Biology
  • Drug Resistance

Background:

  • Multidrug resistance (MDR) in cancer chemotherapy is often due to drug efflux by transporters like P-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP).
  • Novel resistance modifying agents (RMAs) PSC 833, 280-446, and LY335979 are known Pgp inhibitors, but their effects on MRP-mediated resistance are largely uncharacterized.

Purpose of the Study:

  • To investigate the impact of novel RMAs (PSC 833, 280-446, LY335979) on drug resistance mediated by MRP.
  • To determine if these agents can overcome MRP-associated multidrug resistance in cancer cells.

Main Methods:

  • Utilized drug-resistant human leukemia cell lines with defined Pgp and MRP expression profiles (Pgp+/MRP- and Pgp-/MRP+).
  • Measured intracellular daunorubicin accumulation via flow cytometry and fluorescence detection.
  • Assessed drug sensitization and daunorubicin dose-response curves to determine growth inhibition (GI50).

Main Results:

  • All tested MDR phenotypes exhibited significant resistance to daunorubicin.
  • PSC 833, 280-446, and LY335979 effectively sensitized Pgp+/MRP- cells to daunorubicin.
  • PSC 833 and 280-446 increased daunorubicin accumulation and sensitization in Pgp-/MRP+ cells, whereas LY335979 had no effect on MRP-mediated resistance.

Conclusions:

  • Pgp-inhibiting agents demonstrate differential effects on MRP-mediated drug resistance.
  • These findings suggest potential therapeutic strategies by combining Pgp inhibitors with agents that also target MRP to overcome multidrug resistance in cancer patients.

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